Sindbis virus, (an alpha-virus of the Togavirus family), infection produces an acute encephalitis in mice, in which the mortality is age-dependent. Since virus specific immune resonses do not appear to be an important determinant, it is proposed to study non-specific factors which may be important in the acquisition of age-dependent resistance to fatal infection. The immunologically non-specific factors which will be examined are the reticuloendothelial system (RES), natural killer (NK) cells including their relationship to interferon, and complement. Viral clearance from the blood and localization in RES tissues will be studied using intravenous inoculation of radiolabeled infectious virus in young and old mice with and without complement depletion. The age dependence of NK cell induction by sindbis virus will be examined. If NK cell induction is age dependent, adoptive transfer studies will be done in an attempt to alter the course of a fatal infection. Since it has been shown that complement limits viremia and subsequently, amounts of virus in the central nervous system, interactions between complement and Sindbis virus will be studied in vitro as well as in vivo. The activation of the complement system by Sindbis virus and the interaction of complement coated virus with macrophages will be studied in vitro. The role that complement may play in limiting CNS growth of virus will be studied in normal and complement depleted animals infected by the intracerebral route. The role of the terminal complement components will be assessed by comparing the pathogenesis of infection in B10.D2/new line mice (C5-sufficient) and B10.D2/old line mice (C5-deficient). Finally, comparative studies of activation of complement by virus grown on BHK and CEF cells will be performed to determine the role of sialic acid in the activation of complement by virus.